Recent studies show that in both normal and neoplastic tissues, gastrointestinal hormones (GI) and GI growth factors (GF) may cause cell growth by stimulating multiple intracellular tyrosine phosphorylation (TyrP) signaling cascades as well as by transactivation growth factor receptors. However, at present little is known about the ability of many gastrointestinal hormones/growth factors to activate these cascades. During this year we reviewed this subject and the evidence for the ability of various GI peptides to affect the growth of tumors and because of that to be increasingly studied as oncotargets, both for growth inhibition by antagonists and for targets to deliver tumoricidal agents to the neoplasm. We report a study demonstrating that endothelin (ET) can interact with ETA receptors on lung cancer cells to stimulate growth and that this is mediated by transactivation of both epidermal growth factor receptor and ERB2/HER2/Neu activation. The transactivation requires activation of Src, matrix metalloproteinases and generation of oxygen free radicals. Little is known of the role of activation of p21-activated kinases (PAKs), especially the Group 2 PAKs PAK4-6 in mediating actions of GI hormones/neurotransmitters. In a study we used pancreatic acinar cells, which are highly responsive to number of gastrointestinal hormones/neurotransmitters to explore the presence, signaling cascade and role PAK4 to mediate secretion and growth cascades in these cells. We found that only PAK4 of the type II PAK family was present in pancreatic acinar cells and that it was activation of pancreatic hormones/neurotransmitters/ growth factors in acinar cells. We found that it was activated by PKC-, Src-, p44/42-, or p38-dependent cascades. Furthermore, its activation was required for both enzyme secretion as well as activation of MAP kinases, which mediate growth cascades in these cells. These results suggest PAK4 should be considered an important signaling molecule for pancreatic acinar physiological responses and, in the future, should be investigated for a possible role in pancreatic acinar pathophysiological responses, such as in pancreatitis.